The farnesyl transferase inhibitor (FTI) lonafarnib improves nuclear morphology in ZMPSTE24-deficient fibroblasts from patients with the progeroid disorder MAD-B

ABSTRACT

Several related progeroid disorders are caused by defective post-translational processing of prelamin A, the precursor of the nuclear scaffold protein lamin A, encoded by LMNA. Prelamin A undergoes farnesylation and additional modifications at its C-terminus. Subsequently, the farnesylated C-terminal segment is cleaved off by the zinc metalloprotease ZMPSTE24. The premature aging disorder Hutchinson Gilford progeria syndrome (HGPS) and a related progeroid disease, mandibuloacral dysplasia (MAD-B), are caused by mutations in LMNA and ZMPSTE24, respectively, that result in failure to process the lamin A precursor and accumulate permanently farnesylated forms of prelamin A. The farnesyl transferase inhibitor (FTI) lonafarnib is known to correct the aberrant nuclear morphology of HGPS patient cells and improves lifespan in children with HGPS. Importantly, and in contrast to a previous report, we show here that FTI treatment also improves the aberrant nuclear phenotypes in MAD-B patient cells with mutations in ZMPSTE24 (P248L or L425P). As expected, lonafarnib does not correct nuclear defects for cells with lamin A processing-proficient mutations. We also examine prelamin A processing in fibroblasts from two individuals with a prevalent laminopathy mutation LMNA-R644C. Despite the proximity of residue R644 to the prelamin A cleavage site, neither R644C patient cell line shows a prelamin A processing defect, and both have normal nuclear morphology. This work clarifies the prelamin A processing status and role of FTIs in a variety of laminopathy patient cells and supports the FDA-approved indication for the FTI Zokinvy for patients with processing-deficient progeroid laminopathies, but not for patients with processing-proficient laminopathies.

KEYWORDS:

• Atypical progeroid syndrome
• LMNA-C588R
• LMNA-D325N
• LMNA-E138K
• LMNA-M540T
• LMNA-R644C
• mandibuloacral dysplasia-type B
• prelamin A
• ZMPSTE24-L425P
• ZMPSTE24-P248L

Acknowledgments

We thank Eric Spear for comments on the manuscript and his assistance in its preparation.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data sharing

The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19491034.2023.2288476

Additional information

Funding

This work was funded by NIH grants to SM [R35GM127073 and R01AG075047] and funding to SM from Eiger Biopharmaceuticals, Inc., which had no role in the design, performance, analysis, or interpretation of the data presented here, nor in the preparation and submission of this manuscript. This work was also funded by a grant from The Progeria Research Foundation to LBG [PRF-2002-MRD].